Genetics Flashcards
Risk of first cousins having child with genetic problems?
5%
What proportion of genetic material is shared between first cousins?
1/8
If a patient has a de novo PTPN11 mutation (Noonan syndrome) how likely is the parents’ second child to have Noonan?
1-2% - possible gonadal mosaicism containing AD mutation
What is the most common mutation for achondroplasia?
c.1138G>A (p.Gly380Arg) variant in the FGFR3 gene on 4p16.3 is the cause in about 98% of individuals
What is the screening test for achondroplasia and what do you see?
- Skeletal survey
- rhizomelic shortening (femur, humerus)
- vertebral scalloping
- horizontal acetabular roof with ‘mickey mouse ear’ iliac wings
- metaphyseal flaring (trumpet bone)
- trident hand
How often is achondroplasia a de novo mutation?
80% - AD mutation
What is the rate of autism in the sibling of an affected individual?
3%
Population risk 0.02-0.04%
What is the most heritable psychiatric disorder?
Bipolar - 65% concordance in monozygotic twins
First degree relative 15%
What does a transcription factor do?
Regulates binding of RNA polymerase
Which type of mutation is the most pathological?
Frame shifting (anything not in a multiple of 3 more likely to frame shift)
PHOX2B mutations are associated with…
Congenital central hypoventilation syndrome
How do you diagnose Prader-Willi?
Methylation analysis of the Prader-Willi critical region.
What are the key features of Stickler Syndrome?
- autosomal dominant, gene mutation causing defect in collagens type II, IX or XI
- midface hypoplasia, Pierre-Robin sequence
- severe myopia, glaucoma, cataracts, retinal detachment
- hearing loss
- hypermobile joints - early arthritis
What can you NOT diagnose on regular karyotype?
Microdeletion
What gene is involved with Friedrich ataxia?
FXN1 (Frataxin) on 9q13 with a GAA repeat expansion in 96% - the size of the repeat on the smaller allele predicts severity
What are the features of Bardet-Biedl syndrome?
- AR, variable genes
- Short, fat, stupid (intellectual disability)
- Retinitis pigmentosa -> vision deteriorates
- Polydactyly
- Hypogonadism
What syndromes are associated with retinitis pigmentosa?
- Bardet-Biedl
- METABOLIC: Kearns-Sayre (mitochondrial ‘red ragged fibre’), Refsum (peroxisomal, high phytanic acid), abetalipoproteinaemia (no VLDL, steatorrhoea)
- Usher (progressively deaf and blind)
- INFECTIVE: neurosyphilis, toxoplasmosis
What are the features of Cornelia de Lange syndrome?
- Mouth like foetal alcohol, but monobrow and upturned nose
- Severe ID and self harm
- Limb abnormalities, IUGR and short
- Cardiac issues
- Gut malrotation
What type of collagen defect can cause both Stickler and Marshall Syndrome?
COL11A1 gene - type XI collagen, also Type II collagen for Stickler
What are the features of Smith-Lemli-Opitz syndrome?
- Microcephalic, micrognathia, micropenis (ambiguous genitalia in males)
- adrenal insufficiency
- syndactyly of 2nd and 3rd toes
- severe intellectual disability
- give cholesterol + bile salts
If you see unilateral facial microsomia (incomplete development of the ear, nose, soft palate, lip, and mandible on one side of the body) you should suspect…
Goldenhar or occulo-auricular-vertebral syndrome
What is the gene implicated in Kabuki syndrome?
MLL2
If you see fuzzy, sparse hair think…
- Menkes
- Netherton if ‘bamboo hair’ and erythroderma
What does DNA polymerase do in PCR?
- Extends the primers once they are affixed to the single strand
If you have a blood film with giant platelets and history of bleeding, then it may be…
- GP1B defect - Bernard Soulier syndrome, defect in vWF receptor
- Distinguish from vWD by the fact that normal plasma doesn’t help.
What gene is Zellweger most associated with?
- PEX1 on long arm 7q21-22
What syndromes are associated with dural ectasia?
- Marfans (major criteria, 60% have)
- NF
- Osteogenesis imperfecta
What are the characteristic facies of Williams syndrome?
“Elfin” facies
- Broad forehead
- Blue eyes with stellate pattern iris
- Short nose with a broad tip, full cheeks
- Wide mouth with full lips and dental issues eg. missing teeth
You see a baby with red, scaly skin, bamboo hair, and who is failing to thrive…
- Netherton syndrome
- Also get lots of allergies
What is the gene associated with ARPKD?
- PKHD1
If you see a baby with a hypothalamic harmatoma, imperforate anus and funny digits (polydactyly/syndactyly) which syndrome do you think of?
Pallister-Hall
Also have kidney issues and bifid epiglottis
What does DNA helicase do?
Unwinds DNA
Which genes are missing in Prader-Willi?
- Paternal imprinting i.e. no Dad copy
- 15q11-13
Which genes are missing in Angelman?
- Maternal imprinting i.e. no Mum copy
- 15q11-13
Which genes are affected in Beckwith-Wiederman syndrome?
- 11p15.5
- Complicated imprinting - loss of IMPRINTING CONTROL is the cause of most cases
- Loss of methylation at IC2 which means paternal overexpression of KCNQ1OT1 (50%)
- Paternal UPD 11 (20%)
- Gain of methylation at IC1 (~5%)
- Mutation of CDKN1C (<5%)
There is a neonate with cleft, polydactyly, holoprosencephaly and possibly and omphalocele who has:
- Patau aka Trisomy 13
What genetic area is involved with Williams syndrome?
7q11.23, elastin gene
What is a microarray for?
- Microarray AKA molecular karyotype: micro-deletion and micro-duplication, copy number variants, homozygosity
- Does NOT detect point mutations, very very small duplications and deletions of DNA segments within a single gene (Fragile X syndrome, for example) or balanced chromosomal rearrangements (balanced translocations, inversions)
For a traditional karyotype, when do we pause cell cycle?
Metaphase/mitotic division - aiming to get maximally contracted DNA to make it easier to see the chromosomes
What do you specifically find on traditional karyotype?
- Karyotype: ring chromosome, extra chromosomes
There is a baby with macrocephaly and fusion of the coronal suture…
- FGFR3-related craniosynostosis/Muenke Sydnrome
Which HLA type is associated with narcolepsy?
- HLADQB1
In which metabolic disorders do you see cherry-red retinal spots?
Usually LIPID STORAGE disorders
- Tay-Sachs
- Farber disease
- GM1 and GM2 gangliosidoses
- Metachromatic leukodystrophy
- Niemann–Pick disease
- Sandhoff disease
- Sialidosis
What is the Angelman phenotype?
“Happy Puppet”
- “Hyper” i.e. hypertonic, hyper-smiling/laughing, hyper-electric (seizure)
- “Retarded” profound mental and growth retardation
- widely spaced teeth
Which are your typical disorders that affect calcium?
- Hypocalcaemia DiGeorge (22q11)
- Hypercalcaemia Williams (7q11)
What are the facies of 22q11?
- Small mouth
- Wide prominent nasal bridge/root
- Small eyes that look far apart due to medial canthi being farther apart
- Round ears, deficient upper helices
What syndromes give you increased risk of coeliac disease?
- Type I diabetes mellitus 4.5% (0.97–16.4%)
- First degree relatives of coeliac patients ≈10%
- Selective IgA deficiency 8%
- Autoimmune thyroiditis 3%
- Down syndrome 5-12%
- Turner syndrome 6%
- William syndrome 10%
What is the typical Williams facial phenotype?
Broad forehead, short nose and full cheeks, an appearance that has been described as “elfin”
